Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control

Sarah A Weiss; Amy Y Huang; Megan E Fung; Daniela Martinez; Alex C Y Chen; Thomas J LaSalle; Brian C Miller; Christopher D Scharer; Mudra Hegde; Thao H Nguyen; Jared H Rowe; Jossef F Osborn; Dillon G Patterson; Natalia Sifnugel; C Mei-An Nolan; Richard A Davidson; Marc A Schwartz; Alexander P R Bally; Dennis K Neeld; Martin W LaFleur; Jeremy M Boss; John G Doench; W Nicholas Haining; Arlene H Sharpe; Debattama R Sen

doi:10.1038/s41590-024-01961-3

Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control

Nat Immunol. 2024 Oct;25(10):1871-1883. doi: 10.1038/s41590-024-01961-3. Epub 2024 Sep 17.

Authors

Sarah A Weiss^{1

2

3

4}, Amy Y Huang^{1

2

3

5}, Megan E Fung^{1

2}, Daniela Martinez^{3

6

7

8}, Alex C Y Chen^{3

6

7

8}, Thomas J LaSalle^{3

6

7

8}, Brian C Miller^{9

10

11

12}, Christopher D Scharer¹³, Mudra Hegde³, Thao H Nguyen^{1

2}, Jared H Rowe^{1

2

14}, Jossef F Osborn^{1

2}, Dillon G Patterson^{1

2}, Natalia Sifnugel^{1

2}, C Mei-An Nolan^{1

2}, Richard A Davidson⁶, Marc A Schwartz^{3

6}, Alexander P R Bally¹³, Dennis K Neeld¹³, Martin W LaFleur^{1

2}, Jeremy M Boss¹³, John G Doench³, W Nicholas Haining^{3

14

15}, Arlene H Sharpe^{16

17

18

19}, Debattama R Sen^{20

21

22

23}

Affiliations

¹ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
² Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
⁵ Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁸ Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Medicine, Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA.
¹⁴ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁵ ArsenalBio, San Francisco, CA, USA.
¹⁶ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. [email protected].
¹⁷ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
¹⁸ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
¹⁹ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
²⁰ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
²¹ Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
²² Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
²³ Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. [email protected].

PMID: 39289557
PMCID: PMC11528687 (available on 2025-04-01)
DOI: 10.1038/s41590-024-01961-3

Abstract

PD-1 is a key negative regulator of CD8⁺ T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects. Here, we functionally interrogated the epigenetic regulation of PD-1 using a mouse model with deletion of an exhaustion-specific PD-1 enhancer. Enhancer deletion exclusively alters PD-1 expression in CD8⁺ T cells in chronic infection, creating a 'sweet spot' of intermediate expression where T cell function is optimized compared to wild-type and Pdcd1-knockout cells. This permits improved control of chronic infection without additional immunopathology. Together, these results demonstrate that tuning PD-1 via epigenetic editing can reduce CD8⁺ T cell dysfunction while avoiding excess immunopathology.

MeSH terms

Animals
CD8-Positive T-Lymphocytes* / immunology
Enhancer Elements, Genetic / genetics
Epigenesis, Genetic*
Lymphocyte Activation / immunology
Lymphocytic Choriomeningitis / immunology
Lymphocytic Choriomeningitis / virology
Mice
Mice, Inbred C57BL*
Mice, Knockout*
Programmed Cell Death 1 Receptor* / genetics
Programmed Cell Death 1 Receptor* / metabolism

Substances

Programmed Cell Death 1 Receptor
Pdcd1 protein, mouse

Abstract

MeSH terms

Substances

Grants and funding